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ROCHESTER ACADEMY OF MEDICINE

COVID-19 ARCHIVE

Since emerging in Wuhan, China, in December,2019, the COVID-19 epidemic caused by the novel coronavirus SARS-CoV-2 has progressed rapidly into a true global pandemic. Scientists and doctors are working furiously to address all aspects of this new virus: more than 7,000 papers on the pandemic -- covering everything from virology to pharmacology -- have appeared in the past three months. To assist health care professionals in all disciplines working under these continuously evolving conditions to bring this outbreak to a close, the RAOM has created a curated archive of the most critical publications to emerge from the COVID-19 pandemic to this time. The goal of this resource is to bring together vital COVID-19 content for care providers in a user-friendly, accessible format.  To this end, we have assembled the most significant publications, organized by content. To access any publication, copy the DOI and enter it into your browser. The RAOM Archive will be continuously updated with new publications added each week. 

For suggestions, questions, please contact: Rae-Ellen W. Kavey, MD, MPH; rekavey@gmail.com.

TABLE OF CONTENTS - Click Any Link...

Brief Disease Outbreak Narrative                                                              

The Virus                                                                                                

The Disease                                                                                          

Epidemiology                                                                                       

Treatment                                                                                            

Prevention/Vaccine Development                                                        

Prediction Dynamics                                                              

BRIEF DISEASE OUTBREAK NARRATIVE

On Dec. 1st when the first reported case appeared in Wuhan, China, it might have seemed inconsequential, just one patient with a community-acquired pneumonia of unknown etiology. But Wuhan in Hubei province is a major Chinese commerce and transportation hub with a population of more than 11 million people: disease spread of any contagion was inevitable. By Dec. 31st, there were 26 more hospitalized cases with a similar clinical picture with 6 deaths; two-thirds of the patients had direct contact with a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus.  On Dec. 31st, the Wuhan Municipal Health Commission publicly announced the outbreak and alerted the W.H.O.

In the 3 weeks that followed, Wuhan health authorities reported no new information despite identification of the pathogen as a new coronavirus very similar to SARS-CoV by Chinese scientists on January 7th. A Ministry of Health team reported there was no person-to-person transmission and that the outbreak was well controlled after closure of the Huanan market; the outbreak was represented as "preventable and controllable." It was not until definite person-to-person transmission was confirmed with 2019-nCoV cases reported in Thailand and Japan, as well as in Chinese patients with no exposure to the Huanan market that the Ministry of Health confirmed person-to-person transmission -- including multiple cases in local doctors and nurses -- and a national response was finally triggered on January 20. Three days later, on January 23rd, national authorities abruptly placed a complete lockdown on Wuhan, eliminating all forms of transportation and effectively sealing off the city. But by then, an estimated 5 million people had already left the city. By January 25th, confirmed cases in mainland China stood at 2,016 and there were already reported cases, all linked to Wuhan by travel or contact, throughout Asia and in Australia, France, the United States and Sweden. 

The W.H.O. convened an advisory Emergency Committee and on January 30, they concluded the outbreak had become a Public Health Emergency of International Concern. On February 5, W.H.O. announced a $675 million 2019-nCoV preparedness plan to coordinate the international response. At a “Global Research and Innovation Forum” to mobilize international action on Feb. 11-12, the W.H.O. Director-General announced that the illness caused by 2019-nCoV now had an official name: COVID-19; and the International Committee on Taxonomy of Viruses proposed SARS-CoV-2 as the official name for 2019-nCoV.

National and international efforts to slow spread of the epidemic proved fruitless. By Feb. 28, COVID-19 had been reported in 47 countries, with >84,124 cases and 2,862 deaths. On that day, China reported 327 new cases but South Korea with a total of 2337 cases -- the largest number outside of China -- reported 511 new cases. There were increasing numbers of cases in northern Italy, in Iran and in Japan.  And there were cases in three different countries in Africa. At this stage, it was obvious that early Chinese suppression of knowledge about the outbreak had squandered a critical window of opportunity to limit spread of the virus: a true global pandemic was underway.

Home.

THE VIRUS

Tan W, Zhao X, Ma X, et al. A novel coronavirus genome identified in a cluster of pneumonia cases—Wuhan, China 2019−2020. China CDC Weekly 2020; 2: 61–62.

Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382:727-33. Published online Jan 24.  DOI:10.1056/NEJMoa2001017

·      Researchers at the China Center for Disease Control investigating the cause of infection in 3 adults with pneumonia of unknown etiology definitively identified a novel coronavirus from broncho-alveolar lavage specimens using whole-genome sequencing, direct polymerase chain reaction (PCR), and culture on January 7,2020.

·      The 2019-nCoV virus -- now officially known as SARS-CoV-2 -- is physically large among viruses, measuring 125 nanometers in diameter, covered with spiky projections -- the surface spike glycoprotein is critical for binding to host cell receptors and is believed to represent a key determinant of host range restriction.

·      By phylogenetic analysis, the previously unknown virus fell into the betacoronavirus genus, which includes SARS-CoV, MERS-CoV, and a bat SARS-like coronavirus.

·      Novel coronavirus was named 2019-nCoV and formed another clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily.

(Coronaviruses are enveloped non-segmented positive-sense RNA viruses belonging to the family Coronaviridae and the order Nidovirales and are broadly distributed in humans and other mammals. Coronaviruses are ecologically diverse with the greatest variety seen in bats, the suggested reservoir for these viruses.  An important CoV factor is their ability to expand their genetic diversity through ongoing recombination and mutation events. Four CoVs are endemic globally and cause 10% to 30% of mild upper respiratory tract infections in adults. Although most human coronavirus infections are mild, SARS-CoV and MERS-CoV have caused more than 10 000 cumulative cases of severe respiratory disease in the past two decades, with mortality rates of 10% for SARS and 37% for MERS.

 

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Roujian Lu, Xiang Zhao, Juan Li et al. Genomic characterization & epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395: 565–74. DOI: https://doi.org/10.1016/S0140-6736(20)30251-8

·      Next-generation sequencing of samples from bronchoalveolar lavage fluid from 9 pts with SARS-CoV-2 infection; 8/9 had visited the Huanan seafood market in Wuhan

·      Genome sequences were extremely similar, exhibiting >99·98% sequence identity.

·      By phylogenetic analysis, 2019-nCoV was most closely related (88% identity) to 2 bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 & bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China; virus is more distant from SARS-CoV (~79%) and MERS-CoV (~ 50%).

·      Homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.

·      Bats might be the original host of this virus with an animal from the seafood market representing an intermediate host facilitating the emergence of the virus in humans.

·      Structural analysis suggests that 2019-nCoV may bind to the angiotensin converting enzyme 2 receptor in humans.

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South China Agricultural University finds pangolin as a potential intermediate host for new coronavirus. Published Jan. 20,2020. Available at: flutrackers.com › -2019-ncov-new-coronavirus › china-2019-ncov.

·      The chief suspect for intermediate host between bats and humans for SARS-C0V-2 is the pangolin, a small ant-eating creature.

·      Pangolins are prized in Asia as food and medicine and were being sold in the Wuhan Huanan seafood and wild animal market, linked to early cases of 2019-nCoV

·      The genome sequence of the novel coronavirus strain derived from pangolins is 99% identical to SARS-CoV-2.

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Paraskevisa D, Kostakia G, Magiorkinisa G et al. Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event. Infection, Genetics and Evolution 2020; 79. April 20, 2020. https://doi.org/10.1016/j.meegid.2020.104212

·      Full-genomic sequence analysis of the novel corona virus (2019-nCoV).

·      Phylogenetic and recombination analysis within the subgenus of sarbecovirus.

·      Evidence that the 2019-nCoV shows discordant clustering with the BatSARS-like coronavirus sequences.

·      No evidence that 2019-CoV 2 emerged as a result of a recent recombination event.

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vanDorp L, Acman M, Richard D et al. Emergence of genomic diversity and recurrent mutations in SARS-CoV-2.  Infection, Genetics and Evolution (2019). https://doi.org/10.1016/j.meegid.2020.

·      Curating a dataset of 7666 public genome SARS-CoV-2 assemblies allowed analysis of the emergence of genomic diversity over time.

·      Results point to all sequences sharing a common ancestor towards the end of 2019, supporting this as the period when SARS-CoV-2 jumped to its human host.

·      Due to extensive transmission, the genetic diversity of the virus in several countries recapitulates a large fraction of its worldwide genetic diversity.

·      By focusing on mutations which have emerged independently multiple times,198 filtered recurrent mutations in the SARS-CoV-2 genome were identified. 

·      Nearly 80% of recurrent mutations produced non-synonymous changes at the protein level, suggesting possible ongoing adaptation of SARS-CoV-2.

Zheng S, Fan J, Yu F et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020 Apr 21;369:m1443. doi: 10.1136/bmj.m1443.

  • ·      Serial respiratory, stool, serum, and urine samples for RNA viral load collected from 96 consecutive pts with SARS-CoV-2 during hospital course in Zhejiang, China.
  • ·      RNA virus detected in sputum and saliva samples in all pts, 55% in stool, 41% in serum.
  • ·      Median virus duration in stool (22 days, IQR:17-31) was significantly longer than in respiratory (18 days, IQR:13-29) & serum samples (16 days, IQR:11-21).
  • ·      Viral load was higher in pts with severe disease than in those with mild disease.
  • ·      Virus duration was longer in patients older than 60 years and in male patient

Wölfel R, Corman VM, Guggemos W et al.  Virologic assessment of hospitalized patients with COVID-2019. Nature. 2020 Apr 1.                                                               doi: 10.1038/s41586-020-2196-x

  • Detailed virologic analysis of nine cases of COVID-19 showed active replication of the SARS-CoV-2 virus in tissues of the throat /upper respiratory tract à Confirmation of early contagious state due to active pharyngeal viral shedding.

Home.

THE DISEASE

CHINA

Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. Published online on Jan. 24, 2020. doi:10.1016/S0140-6736(20)30183-5.

Case series of the first 41 hospitalized pts infected with 2019-nCoV by Jan 2, 2020:

  • ·      Prodromal phase included fever, dry cough, and malaise.
  • ·      Two-thirds of pts had worked or shopped at a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus.
  • ·      Upper respiratory and GI symptoms were notably infrequent.
  • ·      Common laboratory findings on admission included lymphopenia and bilateral ground-glass opacity on CXR &/or consolidation in chest CT scans.
  • ·      22/41 pts (55%) developed severe dyspnea and 13 (32%) required ICU admission;
  • ·      6 pts died à case-fatality rate of 14·6%. (With true number of infections unknown, fatality rate is likely much lower.)  

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Chan JF-W, Yuan S, Kok K-H et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020 Jan 24; [e-pub].                          https://doi.org/10.1016/S0140-6736(20)30154-9.

Confirmation of person-to-person transmission.

WHO. Daily media briefing on #2019-nCoV. Feb. 7, 2020. Available at: www.who.int/ Coronavirus disease 2019 › Media resources.

In clinical series of culture (+) pts from China, 82% have had mild symptoms, 15% severe, 3% critical. 

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Li Q, Guan X, Wu P et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N Engl J Med. Published January 29, 2020.https://www.nejm.org/doi/full/10.1056/NEJMoa2001316

Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020. Published January 30,2020.               https://doi.org/10.1016/S0140-6736(20)30211-7.

Wang D, Hu B, Hu C et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. Published online February 7, 2020.                                                      http://doi:10.1001/jama.2020.1585.

3 early published series of laboratory-confirmed, hospitalized cases from Wuhan à

  •       Median age: 55-59 yrs with male predominance; no pt <15 yrs.
  • ·      Pts with earlier presentation much more likely had exposure to the Huanan Market.
  • ·      Increasing proportion of cases acquired in hospital by pts or hospital personnel over time, to maximum of 40% in one series.
  • ·      Mean incubation period: 5.2 days, 95th%ile at 12.5 days è resulted in 14 day standard quarantine period
  • ·      Most common clinical symptoms: fever( 80%); dry cough(70%), sob(30% ); myalgias(10%).
  • ·      On CXR &/or CT scan, bilateral pneumonia present in 75% of pts with multiple areas of consolidation and ground-glass opacifications.
  • ·      Median time from 1st symptom to sob was 5 days and to hospital admission was 7 days; ~60% developed ARDS at a median of 8 days S/P first symptom.
  • ·      Mortality ranged from 4 to 17%, predominantly in older patients, due to progressive respiratory and multi-organ failure.
  • ·      Overall, mean mortality estimated at ~2%.

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To KK, Tsang OT, Leung WS et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23. pii: S1473-3099(20)30196-1. doi: 10.1016/S1473-3099(20)30196-1.

Serial respiratory viral load of SARS-CoV-2 in posterior oropharynx saliva samples and serum antibody responses from 23 patients with COVID-19 showed highest viral load at presentation and during the first week of illness with subsequent decline over time.

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Zheng S, Fan J, Yu F et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ. 2020 Apr 21;369:m1443.                                       doi:10.1136/bmj.m1443.

  • ·      Serial respiratory, stool, serum & urine samples for RNA viral load collected from 96 consecutive pts with SARS-CoV-2 during hospital course in Zhejiang province,China
  • ·      RNA virus detected in sputum and saliva samples in all pts, in 55% in stool, in 41% in serum.
  • ·      Median duration of virus in stool (22 days, IQR:17-31) was significantly longer than in respiratory (18 days, IQR:13-29) and serum samples (16 days, IQR:11-21).
  • ·      Viral load was higher in pts with severe disease than in those with mild disease.
  • ·      Virus duration was longer in patients >60 years and in males.

USA

Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382; 10: 929-936.                                               DOI: 10.1056/NEJMoa2001191

  • ·      41 yr old previously healthy male resident of Snohamish county, Washington who returned from a visit to Wuhan, China on January 14,2020, presented to an urgent care center on Jan. 21, 2020  with 4 d hx of fever, cough
  • ·      Because of pt.’s travel and awareness of the new coronavirus, SARS-CoV-2 cultures were obtained and were positive
  • ·      Illness was relatively benign with minimal O2 requirement, no critical events
  • ·      Pt was normally active in the community before presentation and sat in the waiting room for some time before he was seen
  • ·      On Feb.28, the virus in another case in that community was found to be very likely descended from that first case based on  phylogenetic analysis. à These genetic findings suggest that SARS-CoV-2 had been spreading through the community for close to six weeks.
  • ·      Snohamish county is close to Everett, Washington where major early COVID-19 outbreak occurred à local disease spread was occurring in the US beginning in the third week of January.

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Wölfel R, Corman VM, Guggemos W et al.  Virologic assessment of hospitalized patients with COVID-2019. Nature. 2020 Apr 1.                                                               doi: 10.1038/s41586-020-2196-x

Detailed virologic analysis of nine cases of COVID-19 showed active replication of the SARS-CoV-2 virus in tissues of the throat /upper respiratory tract à Confirmation of early contagious state due to active pharyngeal viral shedding.

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Sutton D, Fuchs K, D’Alton M, Goffman D.  Universal screening for SARS-CoV-2 in women admitted for delivery.  N Engl J Med April 13, 2020.                                    DOI: 10.1056/NEJMc2009316

  • ·      Case series: 215 pregnant women who delivered infants at NY-Presbyterian MC screened for COVID-19
  • ·      4 women had fever, all tested (+) for SARS-CoV-2
  • ·      Of 211 women without symptoms, 29(13.7%) tested (+) for SARS-CoV-2 on N/P culture à 87.9% of culture (+) women were asymptomatic
  • ·      Overall, 15% of women presenting for delivery were SARS-CoV-2 (+)
  • ·      Universal testing in asymptomatic women presenting for delivery allows protection of mothers, babies and hospital staff.

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Eliezer M, Hautefort C, Hamel A-L et al. Sudden and Complete Olfactory Loss Function as a Possible Symptom of COVID-19. JAMA Otolaryngol Head Neck Surg. Published online April 8, 2020. doi:10.1001/jamaoto.2020.0832

Case report of sudden loss of olfactory function due to COVID-19 infection with bilateral obstructive inflammation of olfactory clefts on imaging, which severely impaired the olfactory function by preventing odorant molecules from reaching the olfactory epithelium.

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Oxley TJ, Mocco J, Majidi S et al.  Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. Correspondence. N Engl J Med: April 28, 2020                DOI: 10.1056/NEJMc2009787

Case series of 5 COVID-19 pts < 60 yrs whose initial disease presentation was a large vessel ischemic stroke. All presented in NYC in March and early April. Mixed picture of coagulopathy in the group. 5% of Wuhan pts experienced stroke as part of their illness.  Further knowledge pending.

FRANCE

Poissy J, Goutay J, Caplan M et al. Pulmonary Embolism in COVID-19 Patients: Awareness of an Increased Prevalence. Circulation 2020. Originally published 24 Apr 2020. https://doi.org/10.1161/CIRCULATIONAHA.120.047430

Case-series of 107 consecutive COVID-19 ICU pts with pneumonia admitted to a tertiary care center in northern France. 22/107(20.6%) developed a pulmonary embolus (PE) within a median of 6 days (range 1 to 18 days) from ICU admission. Frequency of PE in COVID-19 series was twice as high as comparison group of ICU pts with pneumonia (20.6% vs 6.1%; absolute increase risk of 14.4%, 95%CI 6.1 to 22.8%). At PE diagnosis, 20/22 patients were receiving prophylactic antithrombotic treatment. Of note, median BMI of PE pts was 30 (range:22-53). No additional information provided.

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USA – NYC

Richardson S, Hirsch JS, Narasimhan M et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. Published online April 22, 2020. doi:10.1001/jama.2020.6775

  • ·      Case series of 5700 consecutive pts with culture-proven SARS-CoV-2 infection admitted to 12 hospitals in New York City & environs (in the Northwell Health system) from 3/1/2020 through 4/42020.
  • ·      Median age, 63 years [{IQR}, 52-75; range, 0-107 years]; 39.7% female.
  • ·      At triage, 30.7% of patients were febrile, 17.3% had RR>24 breaths/min, and 27.8% on supplemental oxygen. Rate of respiratory virus co-infection was 2.1%.
  • ·      Most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%) & diabetes (1808; 33.8%). Pulmonary diagnoses were not significant co-morbidities.
  • ·      Outcomes assessed for pts who were discharged or died by study end point.            è During hospitalization, 373 patients (14.2%) (median age, 68 yrs [IQR, 56-78]; 33.5% female) were treated in ICU, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) received dialysis, and 553 (21%) died.
  • ·      For pts requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, & 831 (72.2%) remained in hospital.
  • ·      Mortality was 0% (0/20) for male and female patients younger than 20 years.
  • ·      Mortality rates were higher for male vs female pts at every 10-yr age interval.
  • ·      Mortality rates for those who received mechanical ventilation in the 18-to-65 vs > 65 age groups were 76.4% and 97.2%, respectively.
  • ·      Mortality rates for those in the 18-to-65 and older-than-65 age groups who did not receive mechanical ventilation were 19.8% and 26.6%, respectively.

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Petrelli CM, Jones SA, Yang J et al. Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City. medRxiv 2020. doi: https://doi.org/10.1101/2020.04.08.20057794

  • ·      Cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020.
  • ·      Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death).
  • ·      Among 4,103 Covid-19 patients, 1,999 (48.7%) were hospitalized, of whom 981/1,999 (49.1%) have been discharged home, and 292/1,999 (14.6%) have died or were discharged to hospice.
  • ·      Of 445 patients requiring mechanical ventilation, 162/445 (36.4%) have died.
  • ·      Strongest hospitalization risks were age ≥75 years (OR 66.8, 95% CI, 44.7-102.6), age 65-74 (OR 10.9, 95% CI, 8.35-14.34), BMI>40 (OR 6.2, 95% CI, 4.2-9.3), and heart failure (OR 4.3 95% CI, 1.9-11.2).
  • ·      Strongest critical illness risks were admission oxygen saturation <88% (OR 6.99, 95% CI 4.5-11.0) and elevated inflammatory markers: d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95% CI, 2.6-13.8).
  • ·      In the decision tree for admission, most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200.
  • ·      Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.

ITALY

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Grasselli  G, Zangrillo A, Zanella A et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394

Retrospective case series of all 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the COVID-19 Lombardy ICU Network and treated at one of the 72 ICUs in this network between 2/2/2020 3/18/2020. and March 18, 2020. Median (IQR) age was 63 (56-70) years, 82% male. 68% had > comorbidity & 49% had hypertension. 99% (1287/1300 patients) required respiratory support, including endotracheal intubation in 88% and noninvasive ventilation in 11%; ICU mortality was 26%.

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To KK, Tsang OT, Leung WS et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23. pii: S1473-3099(20)30196-1. doi: 10.1016/S1473-3099(20)30196-1.

Serial respiratory viral load of SARS-CoV-2 in posterior oropharynx saliva samples and serum antibody responses from 23 patients with COVID-19 showed highest viral load at presentation and during the first week of illness with subsequent decline over time.

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Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med.2020.                               DOI: 10.1056/NEJMoa2008457.

  • ·      After 1 resident in a skilled nursing facility tested (+) for SARS-CoV-2, all residents underwent 2 assessments of symptoms and NP/OP testing including real-time RT-PCR, viral culture, and sequencing.
  • ·      Asymptomatic residents who tested positive were reassessed 7 days later.
  • ·      23 days after the first (+) test result, 57/89 residents(64%) tested (+) for SARS-CoV2.
  • ·      In 76 residents who participated in 2 surveys, 27/48 tested (+) and were asymptomatic at the time of testing; 24/27 developed symptoms within 4 days.  
  • ·      Among 64%(+) for SARS-CoV-2, 11 hospitalized &15 died (mortality, 26%).
  • ·      Rapid, widespread transmission of SARS-CoV-2 was demonstrated with more than half of culture (+) residents asymptomatic at the time of testing.

à Infection-control strategies focused solely on symptomatic individuals are not sufficient to prevent transmission of this very highly contagious virus after SARS-CoV-2 introduction into this kind of facility.

Home.

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EPIEPIDEMIOLOGY

Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. Published online on Jan. 24, 2020. doi:10.1016/S0140-6736(20)30183-5.

Case series of the first 41 hospitalized pts infected with 2019-nCoV by Jan 2, 2020          

àTwo-thirds of patients had worked or shopped at a local fish and wild animal market, the Huanan Seafood Wholesale Market suggesting a possible origin for the virus.

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Progress continues in coronavirus trace: Wuhan Market Cultures. By Wang Xiaodong | chinadaily.com.cn Updated: 2020-01-26 14:26.

China Center for Disease Control reported on January 26th that of 585 collected samples from the Huanan market, 33 tested positive for the virus. The 33 samples came from 22 stalls and a garbage vehicle in the market, most in the area where wild animals were traded. Further public results of this investigation are still pending.

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Chan JF-W, Yuan S, Kok K-H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020 January 24 (Epub ahead of print )                               DOI: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiaa077/5739751

First formal report of person-to-person transmissibility in China.

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Zhao S, Lin Q, Ran J et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Inter J Inf Dis 2020.  Published online 30 January 2020.                                       https://doi.org/10.1016/j.ijid.2020.01.050.

Early estimates of the basic reproduction number or R0 for SARS-CoV-2 ranged from 2.2 to 3.6.

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Li Q, Guan X, Wu P et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. N Engl J Med. Published January 29, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2001316

Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020. Published January 30,2020.             https://doi.org/10.1016/S0140-6736(20)30211-7

  • ·      Median age: 55-59 yrs with male predominance; no pt <15 yrs.
  • ·      Pts with earlier presentation much more likely to report exposure to the Huanan Mkt.
  • ·      Increasing proportion of cases acquired in hospital by pts or hospital personnel over time, to maximum of 40% in one series à increasing evidence of importance of person-to-person transmission.

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Holshue ML, DeBolt C, Lindquist S et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med 2020; 382; 10: 929-936.                                               DOI: 10.1056/NEJMoa2001191

  • ·      41 yr old previously healthy male resident of Snohamish county, Washington who returned from a visit to Wuhan, China on January 14, 2020, presented to an urgent care center on Jan. 21, 2020 with 4 d hx of fever, cough
  • ·      Because of pt.’s travel and awareness of the new coronavirus, SARS-CoV-2 cultures were obtained and were positive
  • ·      Illness was relatively benign with minimal O2 requirement, no critical events
  • ·      Pt was normally active in the community before presentation and sat in the waiting room for some time before he was seen
  • ·      On Feb.28, the virus in another case in that community was found to be descended from that first case based on phylogenetic analysis. à These genetic findings suggest that SARS-CoV-2 had been spreading through the community for close to six weeks, beginning in mid-January.
  • ·      Snohamish county is close to Everett, Washington where the major early COVID-19 outbreak occurred à proof that local disease spread was occurring in the US beginning in the third week of January.

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Gonzalez-Reiche AS, Hernandez MM, Sullivan M et al. Introductions and early spread of SARS-CoV-2 in the New York City area. medRxiv 2020.                                  doi: https://doi.org/10.1101/2020.04.08.20056929

  • ·      To identify the early events underlying the rapid spread of the virus in the NYC metropolitan area, investigators sequenced the virus causing COVID19 in 90 patients
  • ·      Phylogenetic analysis of 84 distinct SARS-CoV2 genomes indicates multiple, independent but isolated introductions mainly from Europe and other parts of the United States with limited evidence of direct introductions from China.
  • ·      As early as February 20 (90%CI: January 29 to February 26) (Table 1), an identified virus was inferred to be of domestic origin based on its close relationship with US isolates, including those from the main community transmission in Washington state
  • ·      The earliest sequences include isolates from Italy, Finland, Spain, France, the UK, and other European countries from late February plus a few North American isolates (Canada and US) from the first week of March 2020.
  • ·      The sequenced isolates were spatially distributed throughout all NYC boroughs and 21 neighborhoods providing evidence for community transmission of SARS-CoV2 suggested by clusters of related viruses found in patients living in different neighborhoods of the city.

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Millett GA, Jones AT, Benkeser D et al.  Assessing Differential Impacts of COVID-19 on Black Communities. Manuscript under review - JAMA.

  • ·      Discrete state and city data sources show Black Americans to be at elevated risk for COVID-19 infection and death but the race/ethnicity of 78% of current diagnoses nationally is unknown.
  • ·      Investigators compared COVID-19 cases and deaths in above average (i.e. > 13% of the population) black counties versus all other US counties.
  • ·      Roughly one in five counties nationally is disproportionately black, representing 22% of all U.S. counties but these counties accounted for 52% of coronavirus cases and 58% of COVID-19 deaths.
  • ·      Structural factors including health care access, density of households, unemployment +/- pervasive discrimination and others drive these disparities, not intrinsic characteristics of black communities or individual-level factors.

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Sadoughi S, Saltz R. Pediatric multisystem inflammatory syndrome.  NEJM Journal Watch. May 5, 2020.

At least 64 children in New York state, primarily in NYC and on Long Island, New York, have developed a multisystem inflammatory syndrome related to COVID-19, the New York Times reports. The cases first emerged about a month after a surge in COVID-19 in the region, suggesting "it's a post-infectious immune response," one pediatrician said. Most cases have tested positive either for SARS-CoV-2 or for antibodies to the virus. The syndrome includes persistent fever and features of Kawasaki disease or toxic shock but it is definitively not KD. Many of the children have been admitted to intensive care, where they've received cardiac or respiratory support. None have died. U.K. health officials last week warned clinicians to be on the lookout for this syndrome. The Times notes that cases have also been reported elsewhere in the U.S.

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TREATMENT

Shen C, Wang Z, Zhao F et al.  Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma: Preliminary Communication. JAMA 2020;323(16): 1582-1589.                                                                           doi:10.1001/jama.2020.4783.

Uncontrolled case series of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS) with multiple indicators of disease severity received donor convalescent plasma containing neutralizing antibody. Clinical status and all measures of disease severity improved beginning within 3 days and 3 pats were extubated between 2 and 9 days post infusion.

  • è Promising preliminary findings require RCT evaluation.

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News Release. NIH – NIAID. April 29, 2020.                                                              NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.

Hospitalized patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to  preliminary data analysis from a RCT involving 1063 pts, which began on 2/21/20. Pts who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for pts treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059). More detailed trial results are forthcoming. The trial known as the Adaptive COVID-19 Treatment Trial, or ACTT involved 68 sites, 47 in the U.S. and 21 in countries in Europe and Asia. Remdesivir, developed by Gilead Sciences Inc., is an investigational broad-spectrum antiviral treatment administered via daily infusion for 10 days. Published report pending.

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Magagnoli J, Narendran S, Pereira F et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv 2020. https://doi.org/10.1101/2020.04.16.20065920

  • ·      Retrospective analysis of data of all pts hospitalized with confirmed SARS-CoV-2 infection in all U.S. VA medical centers until April 11, 2020.
  • ·      Patients were categorized based on exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard COVID-19 management. Primary outcomes were death and need for mechanical ventilation.
  • ·      RESULTS: 368 patients were evaluated (HC: n=97; HC+AZ: n=113; No HC: n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.
  • ·      à Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted HR, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted HR, 1.14; 95% CI, 0.56 to 2.32; P=0.72).
  • ·      à No evidence that use of HC, either with or without AZ reduced the risk of mechanical ventilation in patients hospitalized with COVID-19.

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Chloroquine, Hydroxychloroquine Likely Ineffective For COVID-19. CONTAGION  Review: Rachel Lutz. April 30, 2020. (Publication pending)

Chloroquine and hydroxychloroquine likely are not effective against the novel coronavirus, according to a paper published in the May issue of The FASEB Journal. Investigators from Harvard Medical School and Mass General conducted a comprehensive literature review of clinical experiences with chloroquine and hydroxychloroquine. Data through April 22 showed that these drugs reduced viral uptake by cells cultured in a lab but not in patients. The drugs prevent the immune system from completing its vital response to viruses, investigators wrote. The drugs also disrupt the cell-mediated immunity that is critical to controlling a viral outbreak such as the one the world is currently facing. There is a need for caution if using these therapies to treat the coronavirus based solely on the results of lab studies and not human trials. “Current trial results involving chloroquine and hydroxychloroquine are leading to a rapidly diminishing view of their utility for COVID-19.”

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Borba MGS, Almeida-Val FF, Sampaio VS et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Network Open 2020;3(4):e208857. April 24, 2020. doi:10.1001/jamanetworkopen.2020.8857

In this phase IIb randomized clinical trial of 81 pts with COVID-19, an unplanned interim analysis by an independent data safety and monitoring board found that the higher dosage of chloroquine diphosphate was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation. The limited sample size did not show any benefit regarding treatment efficacy. The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloroquine should not be used for treatment of severe COVID-19 because of safety concerns regarding QTc interval prolongation and increased lethality.

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Richardson P, Griffin I Tucker C et al. Baracitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020; 395:e30-e31. February 3, 2020. https://doi.org/10.1016/S0140-6736(20)30304-4.

Application of a proprietary, AI-derived knowledge graph queried by a suite of 2019-CoV derived algorithms enabled identification of a potential therapeutic agent. Baracitinib is an already approved anti-arthritic drug with known antiviral and anti-inflammatory properties which has the potential to inhibit the cellular processes used by the virus in cell infection and to inhibit potential cytokine storm.  Investigator-led studies have been underway since March with a large randomized trial beginning on April 14 in conjunction with Eli Lilly and NIH-USAID. Results anticipated within 2 months.

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Paranjpe I, Fuster V, Lala A et al. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. J Amer Coll Cardiol 2020. May 2020.                                                                                              DOI: 10.1016/j.jacc.2020.05.001

  • ·      Increased thromboembolic events and anecdotal observations of improved outcomes with systemic anticoagulation(AC) have been reported in hospitalized COVID-19 pts
  • ·      àRetrospective analysis of association between administration of in-hospital AC and survival in a cohort of 2773 COVID-19 pts hospitalized in NYC
  • ·      786/2773 pts (28%) received AC a median of 2 days post admission; median AC duration was 3 days.
  • ·      Pts who received AC had significantly more B/L coagulation abnormalities
  • ·      Overall, in-hospital mortality for AC pts was 22.5% with median survival of 21 days vs. mortality of 22.8% and median survival of 14 days for non-AC group.
  • ·      In pts who required ventilation, in-hospital mortality for those who received AC was 29.1% with median survival of 21 days vs. 62.7% mortality with 9 day survival for those who did not received AC.
  • ·      In a multivariable proportional hazards model, longer duration of AC was associated with reduced mortality risk.
  • ·      No increased incidence of bleeding events with AC
  • ·      RCT of systemic AC needed.

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Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020; E-published ahead of print, April 30, 2020. https://doi.org/10.1038/s41586-020-2286-9.

  • ·      Investigators cloned, tagged & expressed 26 SARS-CoV-2 proteins in human cells & identified physically associated proteins using affinity-purification mass spectrometry
  • ·      332 high-confidence SARS-CoV-2-human protein-protein interactions were identified with 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, 28 preclinical compounds).
  • ·      Screening these in multiple viral assays identified 2 sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors.
  • ·      Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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AHJ Danser, M Epstein, D Batlle. Renin-angiotensin system blockers and the COVID-19 pandemic: At present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020 Mar 25;[EPub Ahead of Print],                                                DOI: 10.1161/HYPERTENSIONAHA.120.15082

The angiotensin-converting enzyme 2 (ACE2) protein facilitates the entry of coronavirus-2 into cells. ACE inhibitors do not impact ACE2 as ACE and ACE2 are distinct enzymes. There are no data to support the hypothesis that ACE inhibitors or angiotensin II type 1 receptor blockers increase ACE2 expression and hence increase coronavirus entry. Current evidence does not support the discontinuation of ACE inhibitor treatment due to concerns regarding coronavirus infection.

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PREPREVENTION: VACCINE DEVELOPMENT                                                                   (There are at least 108 vaccines in development as of 5/8/2020, 8 in clinical trials)

Lane R.  Carving a path towards a COVID-19 vaccine. Lancet April 18, 2020; 395:1247.                                                                                                                         DOI: https://doi.org/10.1016/S0140-6736(20)30796-0  

  • ·      Post SARS-CoV-2 genome sequence availability, Oxford University team used recombinant DNA techniques to create a vaccine with SARS-CoV-2 antigen embedded in a primate adenovirus vector.
  • ·      The vaccine includes Spike glycoproteins genetic material, a surface protein from SARS-CoV-2 responsible for virus binding to host cell ACE2 inhibitors.
  • ·      Investigators hope to engender an immune response to the Spike protein that will prevent SARS-CoV-2 from entering human cells and causing infection.
  • ·      ChAdOx1-derived vaccines have already been given to >320 people to date, with consistent reports of safety and tolerability and no major adverse events.
  • ·      RCT of the potential vaccine -- ChAdOx1 nCoV-19 -- in 1100 volunteers has begun with results anticipated in 2-6 months. Participants are randomized to the trial vaccine or a control meningitis vaccine.
  • ·      Main outcome is assessment of effectiveness, safety, and immune responses to the vaccine. COVID-19 cases in the 2 groups will be compared.
  • ·      The Serum Institute of India—the world’s largest producer of vaccines—announced plans to make 40 million doses of hAdOx1 nCov-19 beginning prior to trial results.

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Gao Q, Bao L, Mao H et al.Rapid development of an inactivated vaccine for SARS-CoV-2. bioRxiv 2020.                                     https://doi.org/10.1101/2020.04.17.046375

  • ·      Researchers from Sinovac Biotech, a privately held Beijing-based company, gave two different doses of their COVID-19 vaccine to a total of eight rhesus macaques.
  • ·      Three weeks later, the group introduced SARS-CoV-2 directly into the monkeys’ lungs à none developed a full-blown infection.
  • ·      The purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) conferred complete protection in these non-human primates against multiple SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology. Phase 1-2 studies underway.

[To quickly obtain phase 2 & 3 data, investigators may ask regulatory agencies in multiple countries for emergency authorization to give the vaccine to high risk individuals. The DRC in 2018 began to widely use an experimental Ebola vaccine under that status and evidence suggests it significantly helped curb that epidemic.]

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PREDICTION DYNAMICS

Kissler SM, Tedijanto C, Goldstein E, et al. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 2020 Apr 14. doi: 10.1126/science.abb5793. [Epub ahead of print.]

Theoretical transmission dynamics based on modelling including possible contributions of seasonality, duration of immunity, and cross-protection from prior infection with other beta-coronaviruses in common circulation (HKU1 and OC43). Scenarios assess the effects of the length (short=4 weeks to indefinite) & strength (0–60% reductions in Ro) of social distancing.

Baseline seasonality and immunity info:

  • ·      Seasonal coronaviruses circulate from autumn to early spring in temperate regions
  • ·      High levels of seasonality àsmaller initial peak, but larger wintertime outbreaks
  • ·      Immunity to these viruses (HKU1 and OC43) wanes rapidly, over ~1 year
  • ·      Some cross-protection exists between these 2 viruses à ? also SARS-CoV-2
  • ·      SARS-CoV-2 can proliferate at any time of the year (as we are seeing now)
  • ·      If immunity is not permanent, SARS-CoV-2 will eventually enter regular circulation as a fifth seasonal coronavirus
  • ·      If immunity permanent, SARS-CoV-2 will disappear in a few yrs 2o to herd immunity.

Modeling results:                                                                                                                           Social distancing without seasonality:

  • è Short durations of social distancing displace cases into the near future
  • è Longer durations of higher-intensity social distancing reduce case burden in the near term, but result in significant outbreaks during autumn and winter
  • è Permanent social distancing of moderate to high intensity works well to keep SARS-CoV-2 at bay but difficult & unpleasant to sustain

Social distancing + seasonality:

  • è Short durations of social distancing slightly delay peaks of COVID-19, but result in high overall infection rates
  • è Longer durations of social distancing push the peaks into the winter months and increase the overall infection rate
  • è Intermittent social distancing, based on good surveillance, may be needed to keep case load in check until vaccines are available or a sufficient percentage of the population has been infected & herd immunity is achieved

(There are many reported theoretical models of disease transmission dynamics going forward – these will be added as they are published.)

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